TUMOR-ASSOCIATED ANTIGENS
Work with experimental animals, particularly rodents, has shown that most tumors induced by oncogenic viruses express antigens encoded by the viral genome, and that immunization with these antigens can lead to rejection of a subsequent challenge of tumor cells induced by the same virus. Although much of this work was done with laboratory strains of virus, such as SV40, polyoma virus, and Friend, Moloney, or Rauscher murine leukemia viruses, horizontal and vertical transmisison of oncogenic viruses in nature have been demonstrated; indeed a commercial vaccine against virus-induced feline leukemia and sarcoma is now available.
By contrast, a viral etiology of most human cancer has not been demonstrated. Notable exceptions are hepatitis virus (hepatoma), herpes simplex virus (cervical carcinoma), and Epstein Barr virus (nasopharyngeal carcinoma). However, during the past two decades it has been established that some human tumor cells express tumor antigens, i.e., antigens that distinguish the tumor cells from their normal cellular counterparts; some patients mount cell-mediated or humoral immune responses against these antigens (Hellstrom et al. 1968, Nature, 220:1352; Morton et al., 1968, Science 162: 1279-1281; Shiku et al., 1976, J. Exp. Med. 144: 873-881). Some of the targets of these immune responses are oncofetal or differentiation antigens encoded by the human genome (Hellstrom et al., 1970, Int. J. Cancer 6: 346-351).
Until recently the molecular nature of the tumor antigens was unknown, and the degree of tumor specificity of the immunological reactions was unclear. Attempts to utilize this information in developing cancer diagnostic assays or cancer therapies have bene largely unsuccessful. Since spontaneous tumor regressions are extremely rare, one may also conclude that the immune responses demonstrated in vitro were ineffective in vivo; for example, while antibodies and lymphocytes obtained form a cancer patient may be effective in killing tumor cells in vitro, the immune response of the same cancer patient has no effect in vivo.
The introduction by Kohler and Milstein of the monoclonal antibody technique (1975, Nature 256: 495-497) led to intensified searches for human tumor antigens, since it provided the means to define such antigens, both at the molecular level and with respect to specificity (Hellstrom and Brown, 1979, In "The Antigens", M. Sela, ed., Academic Press, Vol. V:1-66). Over the past several years a large number of tumor-associated antigens have been described, most of which have bene defined by mouse monoclonal antibodies Reisfeld and Sell, eds., Monoclonal Antibodies and Cancer Therapy, UCLA Symposia on Molecular and Cellular Biology, New Series, Vol. 27, Alan R. Liss, Inc. New York, 1985, pp. 1-609. Although virtually all of the antigens which have been well characterized have proven to be oncofetal or differentiation antigens, and their specificity for tumors has been found to be quantitative rather than qualitative, several antigens are sufficiently specific for neoplastic versus normal cells (generally corresponding to a factor of 10 to 1,000 times) to be used as potential targets for identifying tumor cells and for therapy. Human monoclonal antibodies to tumor antigens have also been obtained (Cote et al., 1983, Proc. Natl. Acad. Sci. 80: 2026-2030). This supports the previously cited evidence that some cancer patients mount an immune reaction to their tumors.
More than half of the tumor-associated cell surface antigens so far identified are proteins or glycoproteins encoded by the human genome (rather than by endogenous or exogenous viruses), with the remainder being glycolipids, resulting from abnormal expression or regulation of glyosyl transferases.